Targeting AKT/mTOR May Improve Response to Monoclonal Antibodies in Some Cancers

The insulin-like growth factor (IGF) network plays a central role in regulating tumor cell growth and differentiation, tumor angiogenesis, metastasis, apoptosis, and multidrug resistance. Increased IGF-1 receptor (IGF-1R) expression and circulating IGF-1 are associated with increased risk for development of disease and more rapid disease progression in a number of cancers, including head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC). Although IGF-1R inactivation has antitumor effects, a number of clinical trials of anti–IGF-1R monoclonal antibodies have shown only modest efficacy, with the mechanisms involved in drug resistance remaining undefined.

Korean Study

Shin and colleagues at the College of Pharmacy at Seoul National University, Republic of Korea, recently showed that tumor cells resistant to the anti-IGF-1R monoclonal antibody cixutumumab become sensitive to the drug after suppression of mTOR-mediated protein synthesis or inactivation of the epidermal growth factor receptor (EGFR).1 On the hypothesis that cooperation between EGFR and IGF-1R could cause resistance to inhibitors of a number of individual receptor tyrosine kinases, these investigators assessed the involvement of EGFR signaling in IGF-1R monoclonal antibody resistance.

Treatment of cixutumumab-resistant HNSCC and NSCLC cells with cixutumumab induced activation of Akt and mTOR, resulting in synthesis of EGFR, Akt1, and (antiapoptotic) survivin proteins as well as activation of the EGFR pathway. Targeting of the mTOR pathway with rapamycin or targeting of the EGFR pathway with the anti-EGFR monoclonal antibody cetuximab (Erbitux) resulted in prevention of cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects with cixutumumab in vitro and in vivo.

As stated by the authors, “These data show that resistance to IGF-1R inhibition by [a monoclonal antibody] is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin … [and] suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R monoclonal antibodies in HNSCC and NSCLC.” ■